6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide, potassium salt

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1995-Jul-18 through 1995-Dec-12

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: German testing guidelines of December 1989; European community note for guidance of February 1983 (Council Recommandation 831571)

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

6-methyl-1,2,3-oxathiazine-4(3-H)-one-2,2-dioxide potassium salt

IUPAC Name:

6-methyl-1,2,3-oxathiazine-4(3-H)-one-2,2-dioxide potassium salt

Constituent 2

Reference substance name:

6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide, potassium salt

EC Number:

259-715-3

EC Name:

6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide, potassium salt

Cas Number:

55589-62-3

Molecular formula:

C4H5NO4S.K

IUPAC Name:

potassium 6-methyl-2,2,4-trioxo-3,4-dihydro-1,2λ⁶,3-oxathiazin-3-ide

Constituent 3

Reference substance name:

Acesulfame potassium

IUPAC Name:

Acesulfame potassium

Test material form:

solid: crystalline

Details on test material:

- Name of test material (as cited in study report): Acesulfame K (SunettTM)
- Substance type: sweetener
- Physical state: cyrstalline powder
- Analytical purity: 99.8%
- Impurities (identity and concentrations): fluoride <1 µg/g, arsenic <0.01 µg/g, seleniu < 0.1 µg/g, leasd <0.05 µg/g
- Lot/batch No.: D 01 NAAG 50
- Expiration date of the lot/batch: 1998-Dec-31
- Stability under test conditions: stable

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoechst AG, Kastengrund, Germany
- Age at study initiation: young adult
- Weight at study initiation: males: mean 146.9 - 148.7 g, females: mean 109.3 - 116.6 g
- Fasting period before study: not applicable
- Housing:
- Individual metabolism cages: yes/no
- Diet: libitum (Altromin 1321 powder (Altromin GmbH, Lage, Germany)
- Water: ad libitum (tap water)
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): regularly
- Photoperiod (hrs dark / hrs light): 12 h/12h

IN-LIFE DATES:
From: 1995-Jul 18
To: 1995-Aug-02

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): once for the study duration (2 weeks)
- Mixing appropriate amounts with (Type of food): The final dietary mixtures were prepared by using 1 kg premix, adding the necessary amount of Altromin and mixing for 30 min in a precision mixer to produce the required concentrations (9 000 and 15 000 ppm
- Storage temperature of food: room temperature

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Was analytically verified

Duration and frequency of treatment / exposure:

2 weeks, continuous administration via the diet

Doses / concentrations

Remarks:

Doses / Concentrations:
9000 (males: 855 g, females: 827 g), 15000 ppm (males: 1367 g, females: 1277 g)

No. of animals per sex per dose / concentration:

48

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

- Dose selection rationale: based low subchronic toxicityy
- Rationale for animal assignment (if not random): not applicable (random)

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): serum
- Time and frequency of sampling: during the last 24 h prior to termination at 30 min intervals in each 1 male and 1 female

Statistics:

Not applicable

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

AUC: 9000 ppm: males; 848.2 µg.h/ml, females:933.5 µg.h/ml; 15000 ppm: males 1520.6 µg.h/ml, females: 1671.1 µg.h/ml

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

Cmax: 9000 ppm: males: 55.2 µg/ml, females: 71.0 µg/ml; 15000 ppm: males: 108.0 µg/ml, females: 119.3 µg/ml

Toxicokinetic parameters 3

Test no.:

#3

Toxicokinetic parameters:

other: C (average) 9000 ppm: males: 35.32 µg/ml, females: 38.9 µg/ml; 15000 ppm: males: 63.4 µg/ml, females: 69.6 µg/ml

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Not applicable

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Not applicable

Any other information on results incl. tables

Pharmacokinetic profile:

The level of Acesulfame potasium ranged from 16.1 to 71.0 µg/ml in the 9000 ppm group and from 30.3 to 119.3 µg/ml in the 15000 ppm group. Maximum concentrations were mainly observed during dark hours (18:00 to 6:00), whereas all minimum concentrations were determined during light hours (6:00 to 18:00). This indicates that food intake was predominantely over night.

9000 and 15000 ppm Levels in serum (µg/ml)
Time of the day	9000 ppm male	9000 ppm fernale	15000 ppm male	15000 ppm fernale
01.08. 09:00	31.2	41.4	108.0	56.5
01.08. 09:30	24.0	36.0	54.1	80.3
01.08. 10:00	28.0	35.1	58.7	83.2
01.08. 10:30	31.9	42.1	64.8	68.6
01.08. 11:00	32.3	24.9	74.7	94.9
01.08. 11:30	17.1	29.7	55.6	79.6
01.08. 12:00	23.8	32.8	53.0	71.8
01.08. 12:30	35.3	31.0	76.8	53.4
01.08. 13:00	21.7	39.6	48.9	84.8
01.08. 13:30	26.2	24.0	53.6	38.1
01.08. 14:00	32.3	22.1	39.4	39.7
01.08. 14:30	21.7	21.7	40.5	36.9
01.08. 15:00	35.0	52.4	31.8	49.8
01.08. 15:30	22.8	25.7	40.1	40.7
01.08. 16:00	24.5	16.2	43.6	38.0
01.08. 16:30	22.2	16.1	42.2	46.2
01.08. 17:00	19.3	53.7	34.3	50.8
01.08. 17:30	31.6	20.4	43.2	30.3
01.08. 18:00	35.7	28.9	50.2	55.9
01.08. 1 8:30	38.6	19.4	30.4	36.7
01.08. 19:00	26.0	54.9	91.2	48.3
01.08. 19:30	28.9	24.6	55.1	83.7
01.08. 20:00	36.9	18.6	58.2	46.7
01.08. 20:30	32.8	24.2	36.0	89.6
01.08. 21:00	38.5	37.0	71.4	69.7
01.08. 21:30	35.7	39.5	59.7	52.8
01.08. 22:00	45.4	38.6	77.4	119.3
01.08. 22:30	42.6	50.5	56.3	83.3
01 .08. 23:00	32.6	47.4	63.6	80.0
01.08. 23:30	50.7	45.7	61.3	60.9
02.08. 00:00	54.5	41.8	71.8	106.7
02.08. 00:30	50.0	62.6	75.6	82.4
02.08. 01:00	55.2	63.3	80.5	44.1
02.08. 01:30	46.0	42.9	82.3	95.1
02.08. 02:00	41.8	40.2	84.5	107.8
02.08. 02:30	35.0	71.0	97.0	104.1
02.08. 03:00	31.7	56.5	74.3	93.6
02_08. 03:30	51.9	33.1	66.5	93.9
02.08. 04:00	40.3	31.1	68.6	76.1
02.08. 04:30	38.8	59.3	99.0	69.9
02.08. 05:00	54.6	53.1	82.1	75.9
02.08. 05:30	44.4	51.4	69.2	79.3
02.08. 06:00	45.5	50.1	61.7	88.1
02.08. 06:30	48.0	63.3	79.6	88.8
02.08. 07:00	33.7	31.3	55.9	73.0
02.08. 07:30	31.0	44.9	74.9	56.6
02.08. 08:00	43.3	44.7	74.4	59.7
02.08. 08:30	25.2	31.9	68.7	76.4

 

Dose dependency

The increase of AUC(24h) was virtually proportional to the dose level. The 1.7 fold increase in dose was followed by an 1.8 fofd increase in AUC.

Pharmacokinetic parameters in the serum:

9000 ppm

	Male	Female
C(max, µg/ml)	55.2	71.0
T(max)	01:00	02:30
C(min, µg/ml)	17.1	16.1
T(min)	11:30	16:30
C(av, µg/ml)	35.3	38.9
AUC(0-24, µg.h/ml)	848.2	933.5

 

15000 ppm

	Male	Female
C(max, µg/ml)	108.0	119.3
T(max)	09:00	22:00
C(min, µg/ml)	30.4	30.3
T(min)	18:30	17:30
C(av, µg/ml)	63.4	69.6
AUC(0-24, µg.h/ml)	1520.6	1671.1

 

Sex differences

Remarkable sex differences have not been observed. The levels and consequently also the AUC in female rats were about 10 % higher than in male rats

 

Feed consumption

The mean feed consumption in the second week was in group 1 (9000 ppm) 20.4 and 13.6 g per day in male and female rats, respectively. In group 2 (15000 ppm), 19.9 and 13.0 g were consumed per day in male and female rats, respectively.That corresponds to doses of 854 and 827 mg/kg bw/d (9000 ppm) and to doses of 1367 and 1277 mg/kg bw/d (15000 ppm) in male and female rats, respectively.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
At days 14/15, the AUC(0-24) after feeding of 9 000 ppm was 848.2 µg.h/ml in male and 933.5 µg.h/ml in female rats. At 15000 ppm the AUC(0-24) was 1520.6 µg.h/ml in male and 1671.1 µg.h/ml in female rats.

Executive summary:

Acesulfame potassium was administered to groups of 48 male and 48 female Wistar rats for 2 weeks mixed in the feed at a concentration of 9000 ppm and 15 000 ppm. During the last 24 hours of the study serum samples were taken from 1 male / 1 female animal per group at 30 minutes intervals. Acesulfame K was measured in serum.

This study is assessed as appropriate and valid since it was performed according to internationally accepted testing guidelines under GLP conditions and reporting, assessment and data presentation in the study report was considered as appropriate.

 

At days 14/15, the AUC(0-24) after feeding of 9000 ppm was 848.2 µg.h/ml in male and 933.5 µg.h/ml in female rats. At 15000 ppm the AUC(0 -24) was 1520.6 µg.h/ml in male and 1671.1 µg.h/ml in female rats. The pharmacokinetic parameter AUC (24h) increased proportional to the given dose in the investigated range from 9000 to 15000 ppm. No remarkable sex differences were observed.